The anticancer agent camptothecin and related compounds (FIG. 1) are emerging as an important class of agents useful in the treatment of cancer.
FIG. 1. Clinical candidates and FDA-approved analogs in the camptothecin family of antitumor agents
 AqueousSolubilityCompoundR10R1R2R3SolubleTopotecan/TPTHCH2NH(CH3)2OHH″CDK602HC2H5NHCH(CH3)2HH ″Irinotecan/CPT-11C2H5HH ″GI-147211C/GG-211H InsolubleCamptothecinHHHH″9-ACHNH2HH″9-NC/RubitecanHNO2HH″SN-38C2H5HOHH″DB-67Si(CH3)2C(CH3)3HOHH ″MDCPTHHThese agents display a unique mechanism of action: stabilization of the covalent binding of the enzyme topoisomerase I (topo I), an intranuclear enzyme that is overexpressed in a variety of tumor lines, to DNA. This drug/enzyme/DNA complex leads to reversible, single strand nicks which, according to the fork collision model, promote irreversible and lethal double strand DNA breaks during replication.
The camptothecin class of anticancer agents have exhibited unusual reactivity in vivo, both with respect to drug hydrolysis and blood protein interactions. These factors have hindered the pharmaceutical development and clinical implementation of camptothecins. In terms of hydrolysis, each of the camptothecins shown in FIG. 1 contains an α-hydroxy-δ-lactone pharmacophore. At physiological pH of 7 and above this functionality is reactive, readily converting to the biologically inactive “ring opened” carboxylate form. Thus, as a result of the labile α-hydroxy-δ-lactone pharmacophore, an equilibrium is established between two distinct drug species: 1) the biologically active lactone form where the lactone ring remains closed; and 2) a biologically-inactive carboxylate form generated upon the hydrolysis of the lactone ring of the parent drug. In this invention we describe novel intermediates and prodrugs of camptothecin and related analogs.